A collaborative linkage study of breast cancer families that are not segregating mutations at either the BRCA1 or BRCA2 loci is ongoing. Collaborators in Finland, Sweden and Iceland are working together with NHGRI to add more families to the data set. Genotyping of several candidate regions and a genome wide scan have been performed on these samples. Linkage analysis is ongoing and a paper was published in PNAS in early 2000 suggesting the possibility of an additional locus (BRCA3) about 20 cM from the BRCA2 locus. Fine mapping of positive regions is also ongoing. We have performed additional mutation detection, genotyping and analysis to show that the positive linkage evidence at 13q21-22 is not likely to be due to contamination of our sample by undetected BRCA2 families. Families that did not appear linked to BRCA1, BRCA2 or this novel BRCA3 locus have been genotyped for a genome scan panel of marker loci. Several regions showed some evidence for linkage and the regions with the strongest evidence for linkage are currently being followed up with fine mapping studies. A paper detailing these results has also been published in this fiscal year. This project is ongoing. Additional genotyping of SNP markers in several of these regions has been performed and analyses are ongoing. A second project involving development of better mathematical models for predicting probability of being a carrier of a BRCA1 or BRCA2 mutation was performed in collaboration with Drs. Silvano Presciuttini and Fabio Marroni of the University of Pisa and Dr. Giovanni Parmigiani of Johns Hopkins Bloomberg School of Public Health and a paper was published this fiscal year presenting these results. A new project has been undertaken this year, in collaboration with Dr. Rachel Ellsworth of the Windber Research Institute, and Drs. Henry Lynch and Patrice Watson of Creighton University. In this study, we will examine families with known mutations in BRCA1 and BRCA2 loci to attempt to detect modifier loci and gene-gene interactions. Dr. Bailey-Wilson and her staff have worked with these investigators on study design, power issues and data management in this fiscal year. The families are currently being genotyped for GWS markers and these data will be analyzed in the next fiscal year.